ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.577C>T (p.His193Tyr) (rs876658468)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221478 SCV000273726 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-06 criteria provided, single submitter clinical testing The p.H193Y variant (also known as c.577C>T), located in coding exon 5 of the TP53 gene, results from a C to T substitution at nucleotide position 577. The histidine at codon 193 is replaced by tyrosine, an amino acid with some similar properties. <span style="background-color:initial">This variant is located in the highly-conserved DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9<span style="background-color:initial">). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). <span style="background-color:initial">It has been reported in the database as both a germline mutation in a family with classic Li-Fraumeni Syndrome (LFS), and a somatic mutation in numerous tumors (IARC TP53 database). Another variant at this same amino acid position, p.H193R, has been identified in a patient with LFS, and shown to be severely deficient in transcriptional activation in yeast based assays (Frebourg et al. Am. J. Hum. Genet. 1995 Mar;56(3):608-15; Monti et al. <span style="background-color:initial">Mol. Cancer Res. 2011 Mar;9(3):271-9<span style="background-color:initial">).<span style="background-color:initial"> <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000412758 SCV000491082 pathogenic not provided 2021-08-23 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression ability (Kato 2003, Kotler 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31105275, 15510160, 31500291, 29936259, 27659017, 28599463, 26667234, 23028800, 25343854, 21290192, 21514416, 14559903, 12509970, 21197471, 25655233, 26467027, 26230955, 26068095, 8053493, 23384396, 29979965)
Invitae RCV000809571 SCV000949726 likely pathogenic Li-Fraumeni syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with tyrosine at codon 193 of the TP53 protein (p.His193Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family with Li-Fraumeni syndrome (PMID: 27328919). ClinVar contains an entry for this variant (Variation ID: 230256). This variant has been reported to affect TP53 protein function (PMID: 21514416, 14559903, 12826609). This variant disrupts the p.His193 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 7887414, 22265402, 25945745, 28724667, Invitae), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Database of Curated Mutations (DoCM) RCV000418749 SCV000508486 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429902 SCV000508487 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440111 SCV000508488 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419839 SCV000508489 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430089 SCV000508490 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441207 SCV000508491 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423524 SCV000508492 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434647 SCV000508493 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441502 SCV000508494 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421204 SCV000508495 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431464 SCV000508496 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445008 SCV000508497 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424900 SCV000508498 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432551 SCV000508499 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444740 SCV000508500 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425998 SCV000508501 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436284 SCV000508502 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419469 SCV000508503 likely pathogenic Papillary renal cell carcinoma, sporadic 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426264 SCV000508504 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437380 SCV000508505 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only

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